A method for the use of 5-amino-3-ethyl-1-(m-fluorophenyl)-4-pyrazolecarboxamide

ABSTRACT

The compound 5-amino-3-ethyl-1-(m-fluorophenyl)-4pyrazolecarboxamide and compositions with a pharmaceutically acceptable carrier are described. The compositions are useful as anti-psychoneurotic agents in warm-blooded animals.

United States Patent n 1 Marsico, Jr. et al.

[I 11 3,760,083 [451 Sept. 18,1973

[ A METHOD FOR THE USE OF 5-AMlNO-3-ETHYL-l-(M- FLUOROPHENYL)-4- PYRAZOLECARBOXAMIDE [75] Inventors: Joseph William Marsico, Jr., Pearl River; Leon Goldman, Nanuet, both of N.Y.

[73] Assignee: American Cyanamid Company,

Stamford, Conn.

- [22] Filed: May 1, 1972 [21] App]. No.: 248,991

[52] U.S. Cl. 424/273, 260/310 R [51] Int. Cl A0lk 27/00 [58] Field of Search 424/273; 260/310 R Primary ExaminerStan1ey .l. Friedman Attorney-Ernest Y. Miller [57] ABSTRACT The compound 5-amino-3-ethyl-l--(m-fluorophenyl)-4- pyrazolecarboxamide and compositions with a pharmaceutically acceptable carrier are described. The compositions are useful as anti-psychoneurotic agents in warm-blooded animals.

3 Claims, No Drawings 1 2 METHOD FOR THE USE OF pyrazolecarboxamide. The percentage in the composi- S-AMINO-S-ETHYL-l-(M-FLUOROPHENYL)-4- tion and preparations may, of course, be varied, and PYRAZOLECARBOXAMIDE may conveniently be between about 2 and 60 percent or more of the weight of the unit. The amount of 5- DESCRIPTION OF THE INVENTION 5 amino 3 ethyl l (m fluorophenyn 4 The novel compound of this invention is 5-amino-3- pyrazolecarboxamide in such therapeutically useful ethyl-l-(m-fiuorophenyl)-4-pyrazolecarboxamide of compositions or preparations is such that a suitable the following formula: dosage will be obtained. This dosage can also be ob- U V v tained by the use of sustained release preparations. Pref l ferred compositions or preparations according to the present invention are prepared so that a dosage unit i CONH form contains between about 1 and about 250 milli- N32 grams of the 5-a mino-3-ethyl-1-(m-fluorophenyl)-4- N pyrazolecarboxamide.

I The pharmaceutical preparations such as tablets, pills, dragges, and the like may contain the following: a binder such as gum tragacanth, acacia corn starch, or gelatin; a disintegrating agent such as corn starch, potato starch, alginic acid, or the like; a lubricant such as V acids Such as tearic acid magnesium tea -ate talc or the a drobl'omlc. hydrochloric, P p Sulfuric, citric, sweetening agent such as sucaryl or saccharin may be tartaric and the like. It is a colorless crystalline solid added as we asflavoring such as peppermint of which is soluble in organic solvents such as methanol, intergreen or cherry flavoring. ethanol, acetone, 'ethyl acetate, benzene, propylene The 5-amino-3-ethyl-l-(m-fluorophenyl)4- gl col and the like, but only very slightly soluble in wapyrazolecarboxamide is a valuable anti-psychoneurotic ter. The salts are Soluble in Wat r and g ner lly in yagent of low toxicity. It has a similar profile of activity droxylic solvents. on the central nervous system of warm-blooded ani- The active compound of the present invention is premals as does a reference drug such as chlordiazepoxide; pared by the reaction sequence shown below: namely, depressant activity as measured by impairment NC oozHt cN N N -r NO 002115 NH; 2

Thus, m-fluorophenylhydrazine is condensed with (lof rod-walking ability (ataxic effect), reduction of locoethoxypropylidene )malononitrile in an organic solvent motor activity, protection against strychnine shock and such as ethanol to yield 5-amino-3-ethyl-l-(mprotection against electroshock. fl p ny -py Whliih is y For measurement of ataxic effect, compounds are adlyzed to produce the d sir d -amin -B- hyI- ministered intraperitoneally in a 2 percent starch vehifluoro-phenyl)-4-pyrazolecarb0xamide. mFlu0r0- cle to groups of six mice at three or more graded dose phenylhydrazine may be used as the free base in the relevels. At 15-minute and 30-minute intervals after action, or may be generated in situ by utilizing a mixtreatment, each animal is placed on the midpoint of a ture of m-fluorophenylhydrazine hydrochloride and sohorizontal steel rod (1.55 cm. in' diameter and about 6 dium acetate. The hydrolysis of the carbonitrile to the dm. in length), positioned 45.7 cm. above the surface carboxamide may be accomplished with alkali such as of the table, and forced to walk toward a platform at sodium hydroxide or with acid such as concentrated either end of the rod. The criterion of inability to persulfuric acid. form this act is consistent slipping to the side or falling The 5-amino-3-ethyl-l-(m-fluorophenyl)-4- off the rod. The effective dose for reduced rod-walking pyrazolecarboxamide of the present invention is highly ability (RWD is calculated or approximated from the active in the treatment of psychoneurosis in warmdata, and the time of peak effect is estimated from the blooded animals. It is useful in doses ranging from data. The compound 5-amino-3-ethyl-l-(mabout 1 to 100 mg. per kilogram per day of warmfluorophenyl)-4-pyrazolecarboxamide was found to blooded animal. The preferred range of dose is usually e so f 5 g-l gof body weight. Chlordiazl to 50 mg. per kilogram per day. epoxide, a clinically active anti-psychoneurotic ring,

For therapeutic administration, the 5-amino-3-ethylhad RWD of 16 mg./kg. of body weight. 1-(m-fluorophenyl)-4-pyrazolecarboxamide of this in- To determine reduction of locomotor activity onevention may be incorporated with excipients and used, half of the RWD dose is given intraperitoneally to for example, in the form of tablets, dragees, capsules, each mouse in groups of five. At the time of peak efsuppositories, liquids, elixirs, emulsions, suspensions, feet, as determined above, each group of mice is put syrups, chocolate, candy, wafers, chewing gum, soluinto the actophotometer for a period of five minutes tions for parenteral administration, or the like. Such and the motor activity counts were recorded and corncompositions and preparations should contain at least pared to controls. The compound is administered to ad- 0.1 percent of 5-amino-3-ethyl-1-(m-fluorophenyl)-4- ditional groups of five mice at graded doses and tested similarly. The dose (MDD that caused a 50 percent reduction in motor activity is estimated. The S-amino- 3-ethyll m-fluorophenyl )-4-pyrazolecarboxamide was found to have MDD of 28 mg./kg. of body weight. Chlordiazepoxide had MDD of 28 mg./kg. of body weight.

One measure of depressant activity is the ability to prevent convulsive seizures in warm-blooded animals, e.g., mice, caused by strychnine sulfate [I-l. M. Hanson and C. A. Stone, Animal and Clinical Pharmacological Techniques in Drug Evaluation, Vol. I, J. H. Nodine and P. E. Siegler, Eds., Yearbook Medical Publishers, Inc., Chicago, 111., 1964, p. 317]. Graded dose levels of the compounds are administered intraperitoneally in a 2 percent aqueous starch medium to groups of 10 mice at each dose. Strychnine sulfate, dissolved in aqueous saline, is administered subcutaneously at doses estimated to cause toxic extensor seizures in 95 percent of the mice (0.82 milligrams per kilogram of body weight). Strychnine sulfate is administered 30 minutes after drug treatment. The median effective dose (SP is calculated by the method of J. T. Litchfield and F. Wilcoxon, A Simplified Method of Evaluating Dose-effect Experiments, Journal of Pharmacology & Experimental Therapeutics, Vol. 96, pages 99-1 13 (1949). The 5-amino-3-ethyl-l-(mfluorophenyl)-4-pyrazo1ecarboxamide was found to have SP 50 of 12 mgJkg. of body weight. Chlordiazepoxide had SP of 5 mgJkg.

Another measure of depressant activity is the ability to prevent convulsive seizures caused by electroshock. Compounds are administered intraperitoneally to groups of mice at each of several graded dose levels. Thirty minutes later, mice are subjected to maximal electroshock (60 cycle, 50 mA, 0.2 seconds) via corneal electrodes. The dose (EP which protects 50 percent of the mice from tonic extensor seizures is calculated. The 5-amino-3-ethyl-l-(m-fluorophenyl)-4- pyrazolecarboxamide was found to have EP of 38 mg./kg. of body weight. Chlordiazepoxide had EP of 15 mg./kg. of body weight.

SPECIFIC DESCRIPTION The invention will be described in greater detail in conjunction with the following specific examples showing preparation of the compound of the invention and its use in various formulations.

EXAMPLE 1 Preparation of 5-Amino-3-ethyl-1-(m-fluorophenyl)-4- pyrazolecarbonitrile A mixture of 24.4 g. of m-fluorophenylhydrazine hydrochloride, 22.5 g. of (l-ethoxypropylidene)- malononitrile and 12.3 g. of anhydrous sodium acetate in 300 ml. of absolute ethanol is refluxed for 23 hours, cooled and filtered. The filtrate is evaporated under reduced pressure to give a brown gummy residue. Crystallization from benzene gives, after filtration and washing with benzene, 22.2 g. of light tan crystals, melting point 128-131C. Recrystallization of a 5.00

g. sample from 50 ml. of benzene using activated charcoal gives 3.24 g. of 5-amino-3-ethyl-1-(mfluorophenyl)-4-pyrazolecarbonitrile as colorless crystals, melting point l30--132C.

EXAMPLE 2 Preparation of 5-Amino-3-ethyl-1-(m fluorophenyl)-4- pyrazolecarboxamide A mixture of 6.50 g. of 5-amino-3-ethyl-1-(mfluorophenyl)-4-pyrazolecarbonitrile, 140 ml. of 2N sodium hydroxide and 140 ml. of absolute ethanol is heated under reflux for 6.5 hours and then evaporated under reduced pressure until an oil separates. A few drops of ethanol are added and crystallization occurs. After chilling, the nearly colorless crystals are removed by filtration, washed with water and air-dried to give 5.25 g. of product, melting point 1 141 16C. The crystals are dissolved in dichloromethane and chromatographed over silica gel. The column is eluted with ether (200 ml. cuts) and cuts 3--9 are combined and the solvent is removed by evaporation under reduced pressure. The residual crystalline solid (4.37 g.) is recrystallized from acetone-hexane to give 2.79 g. of 5-amino-3- ethyll m-fluorophenyl )-4-pyrazolecarboxamide as colorless crystals, melting point 124.5-l26C.

EXAMPLE 3 Preparation of 50 mg. Tablets Per Tablet For 10,000 Tablets 0.050 g. S-Arnino-3ethyl-1-(r n-fluoro- 500 g.

phenyl)-4-pyrazolecarboxamide 0.080 Lactose 800 0.010 Corn Starch (For Mix) 0.008 Corn Starch (For Paste) 80 0.148 g. (total) (total) 1480 g. 0.002 g. Magnesium Stearate 20 g. 0.150 g. (total) (total) 1500 g.

The active ingredient, lactose and corn starch (for mix) are blended together. The corn starch (for paste) is suspended in 600 ml. of water, and heated with stirring, to form a paste. This paste is then used to granulate the mixed powders. Additional water is used, if necessary. The wet granules are passed through a No. 8 hand screen and dried at F. The dry granules are then passed through a No. 16 screen. The mixture is lubricated with 1 percent magnesium stearate and compressed into tablets in a suitable tableting machine.

EXAMPLE 4 Preparation of Oral Syrup Ingredient Amount Active ingredient: 5-Amino-3-ethyll -(m-fluorophenyl )-4- pyrazole-carboxamide 500 mg. Sorbitol solution (70% NF.) 40 ml. Sodium benzoate mg. Saccharin 10 mg. Red Dye (FD. & C. No. 2) 10 mg. Cherry flavor 50 mg. Distilled water, q.s. ad 100 ml.

The sorbitol solution is added to 40 ml. of distilled water and the active ingredient is suspended therein. The saccharin, sodium benzoate, flavor and dye are added and dissolved in the above solution. The volume is adjusted to 100 ml; with distilled water. Each ml. of syrup contains 5 mg. of drug.

Other ingredients may replace those listed in the above formulation. For example, a suspending agent such as bentonite magma, tragacanth, carboxymethylcellulose or methylcellulose may be used. Phosphates, citrates, or tartrates 'may be added as bufi'ers. Preservatives may include the parabens, sorbic acid and the like and other flavors and dyes may be used in place of those listed above.

EXAMPLE 5 Preparation of Parenteral Solution in a solution of 700 ml. of propylene glycol and 200 ml. of water for injection is dissolved 20.0 g. of 5- amino-3-ethyl-l-(m-fluorophenyl)-4- pyrazolecarboxamide with stirring. After dissolution is complete, hydrochloric acid is added to adjust the pH to 5.5 and the volume is made up to 1000 ml. with distilled water. The formulation is filtered through a 0.22 micron sterilizing filter, filled into 5.0 ml. ampoules, each containing 2.0 ml. (representing 40 mg. of drug), and sealed under nitrogen.

EXAMPLE 6 A comparison of the present compound with related compounds in the various activities is shown in the following table.

CNS activity p-F No CNS depression 1 p-F No CNS symptoms m-Cl 000 38 100 p-Cl 100 50 8 50 -Br 100 50 19 50 100 54 100 H 100 100 100 H 100 58 100 CN Et m-F 100 50 50 50 Chlordiazepoxide 16 28 5 15 l In preliminary observations screen.

In general, the first compound (present invention) is 

2. A method in accordance with claim 1, wherein the therapeutic composition contains 5-amino-3-ethyl-1-(m-fluorophenyl)-4-pyrazolecarboxamide.
 3. A method in accordance with claim 1, wherein the non-toxic acid addition salt is 5-amino-3-ethyl-1-(m-fluorophenyl)-4-pyrazolecarboxamide hydrochloride. 